Identification of antigenic epitopes of thyroperoxidase, thyroglobulin and interleukin-24. Exploration of cross-reactivity with environmental allergens and possible role in urticaria and hypothyroidism.

BACKGROUND: Human proteins such as interleukin-24 (IL24), thyroperoxidase (TPO) and thyroglobulin (Tg) are targets of IgE or IgG autoantibodies. Why these proteins are recognized by autoantibodies in some patients with chronic spontaneous urticaria (CSU) or hypothyroidism is unknown. OBJECTIVE: Through in silico analysis, identify antigen patches of TPO, Tg and IL24 and compare the sequences of these human proteins with some prevalent allergens. METHODS: The amino acids sequences of IL24, thyroperoxidase and thyroglobulin were compared between them and with 22 environmental allergens. Phylogenetic studies and multiple pairing were carried out to explore the degree of protein identity and cover. The proteins without 3D structure reported in the database, were modeled by homology with "Swiss Modeller" and compared through PYMOL. Residues conserved and accessible to the solvent (rASA> 0.25) were located in the 3D model to identify possible areas of cross-reactivity and antigen binding. RESULTS: We build a 3D model of the TPO and thyroglobulin protein base on proteins closely related. Five epitopes for TPO, six for IL24 and six for thyroglobulin were predicted. The amino acid sequences of allergens from different sources (Dermatophagoides pteronyssinus, Blomia tropicalis, Betula verrucosa, Cynodon dactylon, Aspergillus fumigatus, Canis domesticus, Felis domesticus) were compared with human TPO, Tg and IL24. The cover and alignments between allergens and human proteins were low. CONCLUSION: We identify possible linear and conformational epitopes of TPO, Tg and IL24 that could be the target of IgE or IgG binding in patients with urticaria or hypothyroidism; These epitopes do not appear to be present among common environmental allergens, suggesting that autoreactivity to these human proteins are not by cross-reactivity.

Evolución del cáncer papilar de tiroides en acromegalia: serie de casos / Evolution of papillary thyroid cancer in acromegaly: case series / Evolução do câncer papilar de tireoide na acromegalia: série de casos

Introducción: La acromegalia se produce por un adenoma hipofisario somatotropo, que secreta una excesiva producción de GH e IGF1, se relaciona con mayor riesgo de tumores malignos, no guardando asociación con un patrón especifico de presentación y el objetivo de este estudio es analizar la evolución del cáncer papilar de tiroides en acromegalia. Casos: Se trata de tres pacientes diagnosticados de carcinoma papilar de tiroides (CPT) con diferente pronóstico, con características faciales, y sintomatología como cefalea, alteraciones del campo visual, alteraciones menstruales, que condujeron a la realización de estudios bioquímicos, de imagen y al diagnóstico de acromegalia. Evolución: La aparición de cáncer de tiroides varía en el tiempo de evolución de la acromegalia, en dos de los casos lo antecedió y en el tercero se presentó a la par con esta patología. La respuesta al tratamiento en el CPT es indeterminada en la primera paciente y \excelente en los otros casos; en una paciente se alcanzó remisión. Conclusiones: la coexistencia de acromegalia con cáncer tiroides es posible, que los cambios acrales, faciales y la sintomatología expansiva del tumor conducen al diagnóstico de acromegalia y que la identificación de malignidades no guarda relación con la evolución de la enfermedad.

Introduction: Acromegaly is produced by a somatotropic pituitary adenoma, which secretes an excessive production of GH and IGF1, it is related to a higher risk of malignant tumors, not being associated with a specific pattern of presentation and the objective of this study is to analyze the evolution of papillary thyroid cancer in acromegaly. Cases report: These were three patients diagnosed with CPT with different prognosis, with facial characteristics, and symptoms such as headache, visual field alterations, menstrual alterations, which led to biochemical and imaging studies and the diagnosis of acromegaly. Evolution: The appearance of thyroid cancer in the time of evolution of acromegaly is different, in two of the cases it preceded it and in the third it was presented alongside this pathology. The re-sponse to treatment in CPT is indeterminate in the first patient and excellent in the other cases; re-mission was achieved in one patient. Conclusions: It is concluded that the coexistence of acromegaly with thyroid cancer is possible, that the acral and facial changes and the expansive symptomatology of the tumor lead to the diag-nosis of acromegaly and that the identification of malignancies is not related to the evolution of the disease.

Introdução: A acromegalia é produzida por um adenoma hipofisário somatotrópico, que secreta uma produção excessiva de GH e IGF1, está relacionada a um maior risco de tumores malignos, não estando associada a um padrão específico de apresentação e o objetivo deste estudo é analisar a evolução de câncer papilar de tireoide na acromegalia. Casos: São três pacientes com diagnóstico de carcinoma papilífero de tireoide (CPT) de prognóstico diferente, com características faciais e sintomas como cefaleia, alterações do campo visual, alterações menstruais, que levaram à realização de estudos bioquímicos, de imagem e diagnóstico de acromegalia. Evolução: O aparecimento do câncer de tireoide varia com o tempo de evolução da acromegalia, em dois dos casos ela o precedeu e no terceiro foi apresentado concomitantemente a esta patologia. A resposta ao tratamento no CPT é indeterminada no primeiro paciente e excelente nos demais casos; a remissão foi alcançada em um paciente. Conclusões: a coexistência de acromegalia com câncer de tireoide é possível, que as alterações acrais e faciais e a sintomatologia expansiva do tumor levam ao diagnóstico de acromegalia e que a identificação de neoplasias não está relacionada à evolução da doença.

Diversity and evolution of the thyroglobulin type-1 domain superfamily.

Multidomain proteins are gaining increasing consideration for their puzzling, flexible utilization in nature. The presence of the characteristic thyroglobulin type-1 (Tg1) domain as a protein module in a variety of multicellular organisms suggests pivotal roles for this building block. To gain insight into the evolution of Tg1 domains, we performed searches of protein, expressed sequence tag, and genome databases. Tg1 domains were found to be Metazoa specific, and we retrieved a total of 170 Tg1 domain-containing protein sequences. Their architectures revealed a wide taxonomic distribution of proteins containing Tg1 domains followed or preceded by secreted protein, acidic, rich in cysteines (SPARC)-type extracellular calcium-binding domains. Other proteins contained lineage-specific domain combinations of peptidase inhibitory modules or domains with different biological functions. Phylogenetic analysis showed that Tg1 domains are highly conserved within protein structures, whereas insertion into novel proteins is followed by rapid diversification. Seven different basic types of protein architecture containing the Tg1 domain were identified in vertebrates. We examined the evolution of these protein groups by combining Tg1 domain phylogeny with additional analyses based on other characteristic domains. Testicans and secreted modular calcium binding protein (SMOCs) evolved from invertebrate homologs by introduction of vertebrate-specific domains, nidogen evolved by insertion of a Tg1 domain into a preexisting architecture, and the remaining four have unique architectures. Thyroglobulin, Trops, and the major histocompatibility complex class II-associated invariant chain are vertebrate specific, while an insulin-like growth factor-binding protein and nidogen were also identified in urochordates. Among vertebrates, we observed differences in protein repertoires, which result from gene duplication and domain duplication. Members of five groups have been characterized at the molecular level. All exhibit subtle differences in their specificities and function either as peptidase inhibitors (thyropins), substrates, or both. As far as the sequence is concerned, only a few conserved residues were identified. In combination with structural data, our analysis shows that the Tg1 domain fold is highly adaptive and comprises a relatively well-conserved core surrounded by highly variable loops that account for its multipurpose function in the animal kingdom.